Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo.

Both mammalian target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are often over-activated in prostate cancer cells and are associated with cancer progression. In the current study, we evaluated the potential anti-prostate cancer activity of INK-128, an ATP-competitive mTORC1/2 dual inhibitor, both in vitro and in vivo. Our results showed that INK-128 exerted potent anti-proliferative activity in established (PC-3 and LNCaP lines) and primary (patient-derived) human prostate cancer cells by inducing cell apoptosis. The latter was evidenced by increase of annexin V percentage, formation of cytoplasmic histone-associated DNA fragments, and cleavage of caspase-3. INK-128-induced prostate cancer cell apoptosis and cytotoxicity were alleviated upon pretreatment of cells with the pan-caspase inhibitor z-VAD-FMK or the specific caspase-3 inhibitor z-DVED-FMK. At the molecular level, INK-18 blocked mTORC1/2 activation in PC-3 cells and LNCaP cells and downregulated mTOR-regulated genes including cyclin D1, hypoxia-inducible factor 1α (HIF-1α), and HIF-2α. ERK-MAPK activation and androgen receptor expression were, however, not affected by INK-128 treatment. In vivo, oral administration of INK-128 significantly inhibited growth of PC-3 xenografts in nude mice. The preclinical results of this study suggest that INK-128 could be further investigated as a promising anti-prostate cancer agent.

[Expression of dynamin-1 and phosphor-dynamin-1 in the hippocampus of children and rats with mesial temporal lobe epilepsy].

OBJECTIVE: To observe the expression of dynamin-1 and phosphor-dynamin-1 in the hippocampus of children and rats with mesial temporal lobe epilepsy (MTLE) and to investigate the roles of dynamin-1 and phosphor-dynamin-1 in the development of MTLE. METHODS: Male Sprague-Dawley rats (aged 25 days) were randomly divided into acute control (AC), acute seizure (AS), latent control (LC), latent seizure (LS), chronic control (CC) and chronic spontaneous seizure (CS) groups. Lithium chloride-pilocarpine was used to induce a rat model of MTLE. The hippocampus samples of 5 children with a pathologically confirmed hippocampal sclerosis who received surgical operation were collected as a human model (HM) group, and the hippocampus samples of 4 dead children (without organic lesion of the hippocampus) were collected by autopsy as a human control (HC) group. The expression of dynamin-1 and phosphor-dynamin-1 in the hippocampus of children and rats with MTLE was measured by Western blot and immunohistochemistry. RESULTS: The Western blot showed that the expression of phosphor-dynamin-1 was significantly lower in the AS and CS groups than in the corresponding control groups (AC and CC groups) (P<0.05). The expression of phosphor-dynamin-1 was significantly lower in the HM group than in the HC group (P<0.05). There were no significant differences in the expression of dynamin-1 among the AS, LS and CS groups and between the HM and HC groups (P>0.05). The immunohistochemical results showed that phosphor-dynamin-1 was highly expressed in the cytoplasm of hippocampal neurons of AC, CC and HC groups, but its expression was significantly reduced in the AS, CS and HM groups (P<0.05). CONCLUSIONS: The expression of phosphor-dynamin-1, not dynamin-1, is downregulated in the hippocampus of children and rats with MTLE during seizures, which suggests that the phosphorylation/dephosphorylation of dynamin-1 may be involved in the development of MTLE.

Comparison of intravesical bacillus Calmette-Guerin and mitomycin C administration for non-muscle invasive bladder cancer: A meta-analysis and systematic review.

The aim of the present meta-analysis was to compare the benefits of Bacillus Calmetter-Guerin (BCG) and mitomycin C in the treatment of patients with superficial bladder cancer. The present meta-analysis analyzed the benefits of BCG and mitomycin C in the treatment of patients with superficial bladder cancer by comparing progression-free survival (PFS) rates in patients treated with either of the drugs following transurethral resection. The Medline, Cochrane and EMBASE databases were searched between January 1966 and August 31, 2014 for studies that investigated the efficacy of the intravesical instillation of chemotherapy in patients with non-muscle invasive bladder cancer who had been treated with transurethral resection. Search terms included: 'Urinary bladder neoplasms', 'superficial bladder cancer' and 'non-muscle invasive bladder cancer'; 'bacillus Calmette-Guerin' or 'BCG'; 'mitomycin C'; and 'intravesical administration'. Sensitivity and data quality analyses were performed. A total of 6 randomized controlled studies were included with 1,289 patients. Complete 5-year PFS data for patients who received intravesical resection and were treated with mitomycin C or BCG was provided for 3 of the 6 studies, which were therefore included in the meta-analysis. The overall analysis revealed a significant benefit of BCG compared with mitomycin C in terms of 5-year PFS rate (odds ratio, 0.53; 95% confidence interval, 0.38-0.75; P<0.001), indicating that BCG was superior to mitomycin C therapy in patients with non-muscle invasive bladder cancer following transurethral resection.